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Kidney Week

Abstract: FR-PO160

JMJD3 Activation Contributes to Renal Protection and Regeneration Following AKI in Mice

Session Information

  • AKI: Mechanisms - II
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Yu, Chao, Tongji University School of Medicine, Shanghai, Shanghai, China
  • Yu, Jianjun, Tongji University School of Medicine, Shanghai, Shanghai, China
  • Zhuang, Shougang, Brown University Warren Alpert Medical School, Providence, Rhode Island, United States
Background

We have recently demonstrated that Jumonji domain-containing protein D3 (JMJD3), a histone demethylase of histone H3 on lysine 27 (H3K27me3), is protective against renal fibrosis, but its role in acute kidney injury (AKI) remains unexplored.

Methods

Murine renal tubular epithelial cells (mRTECs) were treated with GSK or siRNA specific for JMJD3. A folic acid (FA)-induced AKI murine model was created by peritoneal injection of FA at 250 mg/kg and a biliteral I/R murine models were established by occluding with a non- traumatic vascular clamp for 35 minutes in mice.

Results

Injury to the kidney upregulated JMJD3 and induced expression of H3K27me3, which was coincident with renal dysfunction, renal tubular cell injury/apoptosis and proliferation. Blocking JMJD3 activity by GSKJ4 led to worsening renal dysfunction and pathological changes by aggravating tubular epithelial cell injury and apoptosis in both murine models of AKI. JMJD3 inhibition by GSKJ4 also reduced renal tubular cell proliferation and suppressed expression of cyclin E, phosphorylation of CDK2, but increased p21 expression in the injured kidney. Furthermore, inactivation of JMJD3 enhanced I/R- or FA-induced expression of TGF-b1, vimentin and Snail, phosphorylation of Smad3, STAT3 and NF-kB and increased renal infiltration by F4/80 (+) macrophages. Finally, GSKJ4 treatment caused a further downregulation of Klotho, BMP-7, Smad7 and E-cadherin, all of which are associated with renal protection and anti-fibrotic effects.

Conclusion

These data provide strong evidence that JMJD3 activation contributes to renal epithelial tubular cell survival and regeneration after AKI.

Funding

  • Government Support – Non-U.S.